Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
复制标题
乳酸通过稳定树突状细胞中的 HIF-1α 来限制 CNS 自身免疫。
DOI：
10.1038/s41586-023-06409-6
复制
发表时间：
2023
期刊：
影响因子：
64.8
通讯作者：
Li,
中科院分区：
文献类型：
--
作者：
Sanmarco,LilianaM;Rone,JosephM;Polonio,CarolinaM;FernandezLahore,Gonzalo;Giovannoni,Federico;Ferrara,Kylynne;Gutierrez-Vazquez,Cristina;Li,Ning;Sokolovska,Anna;Plasencia,Agustin;FaustAkl,Camilo;Nanda,Payal;Heck,EvelinS;Li,
树突状细胞(DC)在自身反应性致病T细胞的发育和激活中发挥作用。与树突状细胞功能相关的基因变异与自身免疫性疾病有关，因此树突状细胞是此类疾病的有吸引力的治疗靶点。然而，开发针对DC的自身免疫靶向治疗需要确定调节DC功能的机制。在这里，使用单细胞和批量转录和代谢分析，结合细胞特异性基因扰动研究，我们确定了在DC中运行的负反馈调节环路，以限制免疫病理学。具体地说，我们发现，由活化的DC和其他免疫细胞产生的乳酸通过缺氧诱导因子1α(HIF-1α)介导的机制促进NDUFA4L2的表达。NDUFA4L2限制线粒体活性氧物种的产生，这些线粒体活性氧物种激活树突状细胞中XBP1驱动的转录模块，参与控制致病的自身免疫T细胞。我们还设计了一种益生菌，通过激活DC中的HIF-1α-NDUFA4L2信号来产生乳酸并抑制T细胞自身免疫。综上所述，我们确定了调节DC功能的免疫代谢途径，并开发了一种用于其治疗激活的合成益生菌。
Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells,. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders,, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α–NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.